Anti-inflammatory effects and improved metabolic derangements in ob/ob mice by a newly synthesized prenylated benzopyran with pan-PPAR activity

Background and purpose: Selective peroxisome proliferator-activated receptors (PPARs) are widely used to treat metabolic complications; however, the limited effect of PPAR alpha agonists on glucose metabolism and the adverse effects associated with selective PPAR gamma activators have stimulated the development of novel pan-PPAR agonists to treat metabolic disorders. Here, we synthesized a new prenylated benzopyran (BP-2) and evaluated its PPAR-activating properties, anti-inflammatory effects and impact on metabolic derangements. Experimental approach: BP-2 was used in transactivation assays to evaluate its agonism to PPAR alpha, PPAR beta/delta and PPAR gamma. A parallel-plate flow chamber was employed to investigate its effect on TNF alpha-induced leukocyteendothelium interactions. Flow cytometry and immunofluorescence were used to determine its effects on the expression of endothelial cell adhesion molecules (CAMs) and chemokines and p38-MAPK/NF-kappa B activation. PPARs/RXR alpha interactions were determined using a gene silencing approach. Analysis of its impact on metabolic abnormalities and inflammation was performed in ob/ob mice. Key results: BP-2 displayed strong PPAR alpha activity, with moderate and weak activity against PPAR beta/delta and PPAR gamma, respectively. In vitro, BP-2 reduced TNF alpha-induced endothelial ICAM-1, VCAM-1 and fractalkine/CX3CL1 expression, suppressed mononuclear cell arrest via PPAR beta/delta-RXR alpha interactions and decreased p38-MAPK/NF-kappa B activation. In vivo, BP-2 improved the circulating levels of glucose and triglycerides in ob/ob mice, suppressed Tlymphocyte/macrophage infiltration and proinflammatory markers in the liver and white adipose tissue, but increased the expression of the M2-like macrophage marker CD206.

Automated summary

The authors synthesized a new prenylated benzopyran (BP-2) and evaluated its PPAR-activating properties, anti-inflammatory effects, and impact on metabolic derangements. BP-2 displayed strong PPAR alpha activity, moderate activity against PPAR beta/delta, and weak activity against PPAR gamma. In vivo, BP-2 improved glucose and triglyceride levels, suppressed inflammation, and increased M2-like macrophage markers in obese mice.